(551d) Development of a Particle Size Analysis Method for Dry and Wet Granulation

Laser diffraction particle size analysis technique has been used in a wide range of industries. This technique is known for its repeatability, ease of verification, in addition to speed of measurement. In the pharmaceutical industry, it has been used for particle size analysis of drug substances and also some unique specialty pharmaceutical finished products such as microsphere and nanoparticle dosage forms, aerosols, and inhalers. However, this technique has not yet been widely used for measurements of solid dosage forms despite the importance of particle size analysis in drug development and manufacturing of these products. The objective of this study was to develop a particle size analysis method for dry and wet granulation of solid dosage forms using laser diffraction technique.

For method development during this study, a Sympatec HELOS laser diffraction particle size analyzer was used. A typical milled and dried granulation made by high shear wet granulation was chosen as representative granules for the study. Samples were prepared by riffling into 5 g or 10 g portions using a spinning riffler prior to measurements. A 32 factorial design of experiments to include sample sizes of 5 g, 10 g, and 20 g as well as vibration levels at 18%, 22%, and 27% was conducted. Upon completion of the experiments, the RSD values of ten measurements of d10, d50, and d90 for all of the analytical conditions were evaluated. The results showed that a sample size of 10 g and vibration level of 27% provided the optimal testing conditions for dry granulation. The results also showed that vibration level had a larger effect than sample size on the RSD values of measurements. In addition, it was determined that the RSD values were sensitive to vibration levels for 5 g and 20 g sample sizes but not for 10 g sample size while 10 g sample size led to lower RSD at all vibration levels. The method developed in this study showed satisfactory robustness in terms of analytical conditions, repeatability, and reproducibility. During the study, the sample size varied from 8 g to 12 g with dispersion vibration level range of 22-32%. In terms of repeatability (day-to-day variation) by one analyst, the RSD values for d10, d50, d90 measured in three different days were 6.5, 1.6, and 0.7%, respectively. In case of reproducibility (analyst-to-analyst variation), the RSD values for d10, d50, and d90 measured by two different analysts were 2.6%, 3.4%, and 8.3%, respectively.

The method described in this study was successfully developed. It has been so far also proven to be suitable for particle size analysis of solid dosage forms such as wet granulation made with high shear wet granulation, dry granulation made with roller compaction, and direct blending. This study has shown that the pioneering laser diffraction approach can effectively measure the particle growth and agglomeration as well as breakage and attrition dynamics in high shear wet granulation modeling.